Complement receptor type 3 (CR3, CD11b/CD18) serves as a receptor for a number of endogenous substances and infectious organisms, and is involved in adhesion and host defense functions. We determined that signalling via CR3 plays an important role in regulating production of interleukin-12 (IL-12), a key mediator of cell mediated immunity (CMI). We demonstrated with a variety of stimuli a dose-dependent, specific downregulation of IL-12 secretion by human monocytes in vitro following exposure to antibodies to CR3 (anti-CD11b and anti-CD18), as well as to the natural CR3 ligands, iC3b, and Histoplasma capsulatum. CR3 antibodies also suppressed IFN-g production in cultures of human peripheral blood mononuclear cells (PBMC). We determined that one mechanism by which CR3 antibodies may suppress IL-12 production is by the inhibition IFN-g-induced tyrosine phosphorylation. Finally, in a murine model of IL-12 dependent septic shock, we demonstrated that administration of CR3 antibodies leads to suppression of IL-12 and IFN-g in vivo. Our studies thus define a novel role for CR3 in regulating CMI functions via IL-12.